In anatomy, the “lower urinary tract” is a term referring to a route between bladder and external urethral orifice, and it has an urinary storage function of pooling urine and an excretion function of excreting urine.
According to the report of the Standardisation Sub-committee of the International Continence Society, the lower urinary tract symptoms are roughly classified into three groups: symptoms of urinary storage disorder, symptoms of dysuria and post micturition symptoms. Symptoms of urinary storage disorder are the symptoms occurring in the urinary storage phase, for example, increased daytime frequency, nocturia, urgency, urinary incontinence, enuresis and so forth are included. On the other hand, symptoms of dysuria are the symptoms occurring in the voiding phase, for example, slow stream, splitting or spraying of the urine stream, intermittent stream, hesitancy, straining to void, terminal dribble and so forth are included. Post micturition symptoms are the symptoms occurring immediately after micturition, for example, feeling of incomplete emptying, post micturition dribble and so forth are included.
Imbalance between bladder detrusor contractility and bladder outlet urethral closure pressure causes the urinary storage disorder and the dysuria. Namely, the urinary storage disorder arises from an overactive bladder (involuntary detrusor contraction), a decreased bladder outlet resistance, a reduced bladder capacity or a combination thereof. On the other hand, the dysuria arises from an impaired bladder detrusor contractility, an increased bladder outlet resistance or a combination thereof. Consequently, their pathogenic mechanisms and symptoms are distinct from each other.
Although an anticholinergic drug is used as a therapeutic agent for the urinary storage disorder (mainly, overactive bladder) at present, there is concern that it produces increased residual urine or urinary retension resulting from impaired detrusor contractility, dry mouth (depression of salivation), constipation and aggravation of cognitive disorder.
On the other hand, as a therapeutic agent for the dysuria, a medicine for increasing the force of contraction of bladder detrusor (e.g., a cholinergic drug such as bethanechol, an acetylcholinesterase inhibitor such as distigmine and so forth), or a medicine for producing relaxation of urethral smooth muscle and weakening the resistance of urethra (e.g., an α1 receptor antagonist such as tamsulosin, prazosin, alfuzosin, naftopidil, urapidil and so forth) is used. A cholinergic drug causes a bladder muscle to contract at a urinary storage phase also and impairs an urinary storage function of bladder. Moreover, it is contraindicated to pregnant woman, digestive ulcer, organic ileus, asthma and hyperthyroidism since it has side effects such as lacrimation, sweating, gastrointestinal disorder, bellyache and so forth. In view of this, satisfactory medicines have not been found out yet. An acetylcholinesterase inhibitor causes a bladder detrusor to contract whereas it causes a sphincter urethrae muscle to contract and increases the resistance of urethra due to its strong nicotinic action. A voiding efficiency is therefore deteriorated and a clinical effect is insufficient. Further, a risk of high pressure voiding is pointed out. In addition, some acetylcholinesterase inhibitors are not used in therapy since it is short-acting (Non-patent document 1). On the other hand, it is reported that an al receptor antagonist has the effect of improving subjective symptoms such as feeling of incomplete emptying, nocturia and so forth. However, the α1 receptor antagonist has a hypotensive effect such as orthostatic hypotension as side effect so an attention must be paid to use it for therapy.
For the meantime, EP1 involved in the present invention is one of the Prostaglandin E2 (hereinafter, abbreviated as PGE2) receptor subtypes of EP1, EP2, EP3 and EP4 (Non-patent document 2), and it is known that EP1 relates to diuresis (Non-patent document 3). In addition, it is known that an intravesical injection therapy of PGE2 to promote urination is effective on anuretic patients (Non-patent document 4). Therefore, a compound which antagonizes to EP1, namely a EP1 antagonist is considered to be useful as a therapeutic agent of pollakiuria.
Although the relationship between EP1 antagonist and lower urinary tract diseases is disclosed in Japanese Patent No. 3741120, WO2002/15902, WO2003/43655, WO2005/00534, WO2005/10534 and WO2006/121097 on the basis of such findings, these patent documents only disclose that the EP1 antagonist is effective for prevention and treatment of “urinary storage disorder” such as pollakiuria and urinary incontinence. These patent documents neither demonstrate nor suggest substantially that the EP1 antagonist is effective for “dysuria” of which the mechanism of action and symptoms are quite different.
Moreover, the other patent documents (e.g., EP878465, WO98/27053, WO92/19617, WO96/06822, WO97/00863, WO99/47497, WO2000/20371, WO2001/19814 and WO2001/19819) which disclose the EP1 antagonist involved in the present invention do not disclose at all that the EP1 antagonist is effective for dysuria.
[Non-patent document 1] Takamichi Hattori, Kosaku Yasuda. “Shinkeiseiboukou no Shindan to Chiryo” 2nd edition, pp. 105-106, Igakushoin.
[Non-patent document 2] J. Lipid Mediat. Cell Signal., 1995; 12: 379-391.
[Non-patent document 3] General Pharmacology, 1992; 23 (5): 805-809.
[Non-patent document 4] European of Urology, 1978; 4 (5): 366.